clinical conundrums: choosing the best management approaches in patients with ovarian cancer thomas...

Clinical Conundrums: Choosing the Best Management Approaches in Patients With Ovarian Cancer

Thomas J. Herzog, MDDirector, Division of Gynecologic OncologyColumbia University College of Physicians and SurgeonsNew York, New York

This program is supported by an educational grant from

clinicaloptions.com/oncologyChoosing the Best Management Approaches in Patients With Ovarian Cancer

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Controversies in the Treatment of Newly Diagnosed Ovarian Cancer


Ovarian Cancer: Initial Chemotherapy

Standard frontline chemotherapy is paclitaxel 175 mg/m2 plus carboplatin AUC 6-7, every 21 days for 6 cycles

Result of several studies over last decade

– GOG 111[1] and OV 10[2]: paclitaxel/cisplatin vs cyclophosphamide/cisplatin

– GOG 158[3] and AGO OVAR-3[4]: carboplatin instead of cisplatin

1. McGuire WP, et al. N Engl J Med. 1996;334:1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92:699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21:3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95:1320-1329.

What About Alternative Taxane Therapy?


*Similar results for patients with CA-125 elevation only.

Vasey P, et.al. J Natl Cancer Inst. 2004;96:1682-1691.

SCOTROC: Clinical Response*

Outcome, % Paclitaxel/Carboplatin(n = 296)

Docetaxel/Carboplatin(n = 300)

CR 28 28

PR 31 30

ORR 59 59

NC 27 29

PD 10 9

Missing/not evaluable 4 4


SCOTROC: Toxicity

Vasey P, et.al. J Natl Cancer Inst. 2004;96:1682-1691.

Adverse Event, % Paclitaxel/Carboplatin

Docetaxel/Carboplatin

P Value

Hematologic toxicity (grades 3-4 )

Neutropenia 84 94 < .001

Thrombocytopenia 10 9 .595

Anemia 8 11 .112

Platelets 11 10 .27

Neuropathy (grades 2-4) 30 11 < .001


JGOG: Dose-Dense Wkly Paclitaxel in Stage II-IV

Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy

Accrual: 637 patients (631 intent to treat)

R

ICarboplatin AUC 6Paclitaxel 180 mg/m2 wk x 3

x 6-9

IICarboplatin AUC 6Paclitaxel 80 mg/m2 wk x 3

x 6-9

Katsumata N, et al. Lancet. 2009;374:1331-1338.


JGOG: Dose-Dense Wkly Paclitaxel

OS at 3 yrs: wkly (72.1%) > 3 wkly (65.1%); HR: 0.75 (95% CI: 0.57-0.98; P = .03)

Treatment Arm n Median PFS (mos)

P Value

Carboplatin AUC 6Paclitaxel 180 mg/m2 3 x wkly

319 17.2.015 (HR: 0.714 (95% CI: 0.581-

0.879)Carboplatin AUC 6Paclitaxel 80 mg/m2/wk x 3

312 28.0

Katsumata N, et al. Lancet. 2009;374:1331-1338.

Will Adding a Third Drug Help?


GOG0182: Pac/Carbo vs Triplet or Sequential Doublet Combinations (Ph III) Paclitaxel/carboplatin x 8 (control)

Paclitaxel/carboplatin/gemcitabine x 8

Paclitaxel/carboplatin/PLD (4) x 8

Topotecan/carboplatin x 4 paclitaxel/carboplatin x 4

Gemcitabine/carboplatin x 4 paclitaxel/carboplatin x 4

Closed to accrual September 1, 2004

Bookman MA, et al. J Clin Oncol. 2009;27:1419-1425.


GOG0182-ICON5: PFS

Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. Bookman MA, et al. J Clin Oncol. 2009;27:1419-1425.

1.00

0.75

0.50

0.25

00 12 24 36 48 60 72

Pro

po

rtio

n o

f P

atie

nts

A

chie

vin

g P

FS

Mos Since Randomization

CPCPGCPDCT → CPCG → CP

TreatmentCPCPGCPDCT → CPCG → CP

Cancer178177199174173

Prog686687663687688

Total864864862861861

HR1.0081.0060.9841.0661.037

(95% CI)Reference Arm(0.924-1.143)(0.884-1.095)(0.958-1.186)(0.932-1.253)

P

.610

.796

.239

.503

Events Adjusted HR

Patients at risk, n

864864862861861

565579574547563

284275277259255

174153162154153

8068636778

2727322723


GOG0182-ICON5: Overall Survival

1.00

0.75

0.50

0.25

00 12 24 36 48 60 72

Pro

po

rtio

n o

f P

atie

nts

A

chie

vin

g O

S


CPCPGCPDCT → CPCG → CP

TreatmentCPCPGCPDCT → CPCG → CP

Alive391399424394361

Dead473465438477500

Total864864862861861

HR1.0001.0060.9621.0611.114

(95% CI)Reference arm(0.895-1.144)(0.836-1.085)(0.925-1.194)(0.982-1.264)

P

.923

.462

.447

.093

Events Adjusted HR

Patients at Risk, n

864864862861861

780780762778773

625622592593589

426424425423395

203214209200203

7270807366

Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. Bookman MA, et al. J Clin Oncol. 2009;27:1419-1425.


Other Recent 3-Drug Frontline Trials

1. Du Bois A, et al. J Clin Oncol. 2006;24:1127-1135. 2. Kristensen G, et al. ASCO 2002. Abstract 805. 3. Scarfone G, et al. ASCO 2006. Abstract 5003. 4. Pfisterer J, et al. J Natl Cancer Inst. 2006;98:1036-1045.5. Herrstedt J, et al. ASCO 2009. Abstract LBA5510. 6. Hoskins PJ, et al. ASCO 2008. Abstract LBA5505.

Group(s) Standard Arm Experimental Arm (s) N Benefit

AGO/GINECO[1] Paclitaxel/carboplatin (TC) TC epirubicin 1282 NS

NSGO/EORTCNCIC CTG[2]

Paclitaxel/carboplatin (TC) TC epirubicin 888 NS

Bolis[3] Paclitaxel/carboplatin (TC) TC topotecan 326 NS

AGO/GINECO[4] Paclitaxel/carboplatin (TC) TC → topotecanconsolidation

1308 NS

AGO/GINECONSGO[5]

Paclitaxel/carboplatin (TC) TC gemcitabine 1742 NS

NCIC CTGEORTC/GEICO[6]

Paclitaxel/carboplatin (TC) Cis topotecan → TC 819 NS

What About IP Therapy?


Role of IP Chemotherapy: Optimally Debulked Ovarian Cancer

1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK, et al. N Engl J Med. 2006;354:34-43.

GOG 104[1]

Improved outcome in CTX cisplatin-treated patients when cisplatin given IP (relative risk: 0.76)

GOG 114[2] Improved outcome in patients when cisplatin administered IP (relative risk: 0.78)

GOG 172[3]

Improved outcome in patients when paclitaxel and cisplatin administered IP(relative risk: 0.73)


GOG 172: Survival

Copyright © 2006 Massachusetts Medical Society. All rights reserved. Armstrong DK, et al. N Engl J Med. 2006;354:34-43.

Outcome IV IP RR P Value

Median PFS, mos 18.3 23.8 0.80 .05

Visible 15.4 18.3 0.81

Micro 35.2 37.6 0.80

Median OS, mos 49.7 65.6 0.75 .03

Visible 39.1 52.6 0.77

Micro 78.2 NA 0.69


GOG 172: Survival

Outcome IV IP RR P Value

Median PFS, mos 18.3 23.8 0.80 .05

Visible 15.4 18.3 0.81

Micro 35.2 37.6 0.80

Median OS, mos 49.7 65.6 0.75 .03

Visible 39.1 52.6 0.77

Micro 78.2 NA 0.69



GOG 172: OS

Mos of Study

Pro

po

rtio

n S

urv

ivin

g

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

00 6 12 18 24 30 36 42 48 54 60

IP therapy

IV therapy

P = .03



IP Compared With IV Chemotherapy Phase III Trials

GOG 104[1] GOG 114[2] GOG 172[3]

1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK, et al. N Engl J Med. 2006;354:34-43.

25

20

15

10

5

0Alberts Markman Armstrong

PFS: % increase

OS: % increase

Will Adding a Targeted Therapy Help?


GOG 218

OvCa III/IV

Subopt

Paclitaxel 175 mg/m2/3 hrsCarboplatin AUC 6

q21d x 6 Bevacizumab* Day 1 x 5

begin cycle 2


q21d x 6Placebo Day 1 x 5

begin cycle 2


q21d x 6Bevacizumab* Day 1 x 5

begin cycle 2

PI: Burger RA

Placeboq 21d

x 15 mos

Placeboq 21d

x 15 mos

Bevacizumab*q 21d

x 15 mos

*Bevacizumab 15 mg/kg IVClinicalTrials.gov. NCT00262847.


ICON 7 (Frontline European Trial)

Stages I-IV ovarian and peritoneal cancer

– Stratified according to stage, optimal status region or country

Carboplatin AUC 6 + Paclitaxel 175 mg/m2/3 hrs q21d x 6

Carboplatin AUC 6 + Paclitaxel 175 mg/m2/3 hrs q21d x 6 + Bevacizumab at 7.5 mg/kgfollowed by Bevacizumab 7.5 mg/kg q21d x 12 mos

Accrual goal: 1444 patientsPrimary endpoint: PFSOther endpoints: OS (10 mos), RR, Toxicity

Translational Research

Tissue and serum markers of angiogenesis

Genomics

DCE-MRI

Quality of life

Health economics

ClinicalTrials.gov. NCT00483782.

RANDOMIZE


Observation

Erlotinib 150 mg/day for up to 2 yrs or until PD

Stage Ic to IV epithelial ovarian cancer, having achieved CR/PR/SD on platinum-based chemo

(6-9 courses)

N = 830Endpoints: PFS and OSRecruitment completed, study ongoing

First-line Maintenance (EORTC) With Translational Substudy


RANDOM I Z E

Prognostic Factors in Ovarian Cancer


Age, Yrs Median PFS, Mos

P Value Median OS, Mos

P Value

< 40 21.8 .03 60.1 < .001

40-50 17.8 47.9

50-59 17.5 47.7

60-69 16.8 44.5

≥ 70 15.8 36.6

Age and Ovarian Cancer Outcome

Winter WE III, et al. J Clin Oncol. 2007;25:3621-3627.


Disease Residual Median PFS, Mos


P Value

Microscopic 33.0 < .001 71.9 < .001

0.1-1 cm 16.8 42.4

> 1 cm 14.1 35.0

Other Prognostic Factors: Debulking Status



Histology Median PFS, Mos


P Value

Serous 16.9 .006 45.1 < .001

Endometrioid 24.8 56.0

Clear cell 11.4 24.0

Mucinous 10.5 14.8

Other Prognostic Factors: Histology



Elderly Patients: Prognostic Analysis

Patient Characteristic HR 95% CI P Value

Age (continuous) 1.07 1.01-1.13 .013

Stage (IV vs III) 3.05 1.58-5.89 .001

Performance score (2-3 vs 0-1) 1.84 0.97-3.51 .064

Symptoms of depression 5.20 2.46-10.99 < .001

Paclitaxel-based chemotherapy(CP vs CC combination)

2.14 1.10-4.15 .025

Trédan O, et al. Ann Oncol. 2007;18:256-262.

Analysis of 2 consecutive trials from the Groupe d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens

This table reports the prognostic factors of poorer survival identified in theproportional hazards model (Cox Regression Model)

Does Having a BRCA Mutation Affect Ovarian Cancer Prognosis?


Ovarian Cancer Relapse: Effect of BRCA Mutations Retrospective cohort study that

included 933 consecutive ovarian cancers at a single institution

Patients restricted to women of Jewish origin (N = 189)

– 88 cases with evidence of germline foundation mutation in BRCA 1 or BRCA2

– Remaining 101 cases included in comparison group

Mean age of diagnosis significantly younger for BRCA1 vs BRCA 2 (54 vs 62 yrs, P = .04)

Median time to recurrence higher in hereditary group vs nonhereditary group (14 vs 7 mos, P < .001)

Improved survival in hereditary group vs nonhereditary group (P = .004)

BRCA mutation status indep. prognostic variable in stage III disease (P = .03)

Boyd J, et al. JAMA. 2000;283:2260-2265.


Ovarian Cancer Survival: Effect of BRCA Mutations 71 Jewish women with epithelial

ovarian cancer tested for 3 BRCA founder mutations; 32 patients analyzed for in vitro chemoresistance

34 pts (48%) had germline BRCA mutations

Disease developed at a younger age in pts with BRCA mutation vs those without (50 vs 59 yrs, P = .001)

Higher response rates to primary therapy in pts with BRCA mutations vs those without (P = .001)

In vitro chemoresistance predicted tumor response to platinum therapy in pts with BRCA mutation (P = .001)

Improved OS in pts with BRCA mutation at advanced stage vs those without (91 vs 54 mos, P = .046)

Longer DFI with BRCA mutation (49 vs 19 mos, P .016)

Cass I, et al. Cancer. 2003;97:2187-2195.


BRCA1 and BRCA2 Mutated Ovarian Carcinomas BRCA1 and BRCA2 are critical proteins in DNA repair via

homologous recombination

BRCA-associated cancers develop after a deletion or mutation of the wild-type allele

Normal nonmalignant cells retain the wild-type allele and intact BRCA function

Cells defective in BRCA1 or BRCA2 are more sensitive to ionizing radiation and platinum compounds

BRCA-deficient cells are dependent on an alternate, PARP-dependent DNA repair pathway

Ongoing and Recently Completed Clinical Trials in Ovarian Cancer


Ovarian, peritoneal or FT cancerStages II-IIIOptimal not required

GOG 9917[1]

IV Paclitaxel 135 mg/m2/3 hrs on Day 1IP Carboplatin (dose esc) on Day 1

q3wks x 6

GOG 9916[2]

IV Paclitaxel 135 mg/m2/3 hrs on Day 1 or IV Docetaxel 100 mg/m2/1 hr on Day 1

Followed byIP Carboplatin (dose esc) on Day 1

IP Paclitaxel 60 mg/m2 on Day 8 q3wks x 6-8

GOG Phase I Trials: IP Carboplatin-Based Regimens

Ovarian, peritoneal or FT cancerstages III-IIIOptimal not requiredOvarian CS allowed

Expanded cohorts with bevacizumab ongoing for both trials cohorts with bevacizumab ongoing for both trials

1. ClinicalTrials.gov. NCT00079430. 2. ClinicalTrials.gov. NCT00085358.


PORT

PK

C

PK

Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6

SLO

PK

Debulkandport

Carboplatin AUC 6

Paclitaxel 60 mg/m2T

IV

IP

Bevacizumab 15 mg/kg

Courtesy of C. Krasner

Dana Farber/Inter-SPORE Treatment Schema


GOG Ovarian Strategy: 252, 262

252Optimal

(≤ 1 cm residual)

262 (under development)Suboptimal

(> 1 cm residual)

IV Paclitaxel 135 mg/m2 on Day 1IP Cisplatin 75 mg/m2 on Day 2IP Paclitaxel 60 mg/m2 on Day 8IV Bevacizumab 15 mg/kg

IV Paclitaxel 80 mg/m2 wklyIP Carboplatin AUC 6IV Bevacizumab 15 mg/kg

IV Paclitaxel 80 mg/m2 wklyIV Carboplatin AUC 6 q3wksIV Bevacizumab 15 mg/kg q3wks

IV Paclitaxel 175 mg/m2

IV Carboplatin AUC 6IV Bevacizumab 15 mg/kg

Bevacizumab q 3 wkMaintenance x 22

Control/Experimental



Every 3 WksCarboplatin AUC 5

Paclitaxel 175 mg/m2

Confirmation Trial

WklyCarboplatin AUC 2Paclitaxel 60 mg/m2

MITO7500 patients




GOG 9923Phase A (cycle repeated q21d for a total of 6 cycles) Phase B

*Bevacizumab started in cycle 2.†ABT-888 will be dose escalated according to the schedule below to determine the MTD; a feasibility phase will follow. During the dose-escalation phase, patients will be enrolled in cohorts of 3 patients each alternating between regimens 1 and 2. During the feasibility phase, 11 additional patients will be enrolled in regimen 1, followed by 11 in regimen 2, with an additional 16 patients following per regimen, if necessary according to the statistical design.

Eligible PatientsNewly diagnosed epithelial ovarian, fallopian tube, or

primary peritoneal cancer FIGO stage II-IV defined surgically

Regimen 1 (Phase A)Paclitaxel 175 mg/m2 on Day 1Carboplatin AUC 6 on Day 1

Bevacizumab 15 mg/kg on Day 1*ABT-888 BID on Days 1-21†

Regimen 2(Phase A)Paclitaxel 80 mg/m2 on Days 1, 8, 15

Carboplatin AUC 6 on Day 1Bevacizumab 15 mg/kg on Day 1*

ABT-888 BID on Days 1-21†

Bevacizumab will be continued as maintenance for cycles 7-22

q21d

ABT-888 Dose Escalation ScheduleDose Level ABT-888 Dose, mg (oral, BID)Level -1 20 mgLevel 1 30 mgLevel 2 50 mgLevel 3 80 mgLevel 4 100 mgLevel 5 150 mgLevel 6 200 mg



OV.21: Optimally Debulked Patients After Neoadjuvant Chemotherapy

Stratification and Randomization

Phase II Portion

Arm 1IV Paclitaxel 135 mg/m2

on Day 1 + IV Carboplatin AUC 5 (measured GFR) or AUC 6 (calculated GFR) on

Day 1; IV Paclitaxel 60 mg/m2 on Day 8; cycles given q21d

x 3 cycles


on Day 1 + IP Cisplatin 75 mg/m2 on Day 1; IP

Paclitaxel 60 mg/m2 on Day 8; cycles given q21d x 3 cycles


on Day 1 + IP Carboplatin AUC 5 (measured GFR) or AUC 6 (calculated GFR) on

Day 1; IP Paclitaxel 60 mg/m2 on Day 8; cycles given q21d

x 3 cycles

Assess Phase II Outcomes(Sample Size = 150)

Proceed to Phase III Portion

Relevance of CA-125 Levels: Placing Novel Data Into Clinical Context


Background: Recurrent Ovarian Cancer

Nearly 70% of advanced stage cancers relapse

Treatment of recurrent disease is complex with a myriad options

Elevation of CA-125 levels may be first indication of recurrent disease

Marker reliability may be extraneously influenced by biologics

Emerging data to inform clinicians on the role of observation vs treatment


Current Questions in Recurrent Disease

How do you define recurrence?

– Physical exam

– Imaging

– Chemical

When do you treat?

– Symptoms

– Imaged lesions

– Chemical


Ovarian Carcinoma: CA-125

Serum glycoprotein (OC-125)

Discovered during a search to boost an immunotherapy (Corynebacterium parvum)[1]

Blood test introduced in 1981

– Present in 82% ovarian cancers; 1% in controls[2]

CA-125 cloned in 2001[3]

– Mapped to chromosome 19 (p13.3)

– Gene: MUC16

– Very large molecule

1. Bast RC, et al. J Clin Invest. 1981;68:1331-1337. 2. Bast RC, et al. N Engl J Med. 1983;309:883-887.3. Yin BW, et al. J Biol Chem. 2001;276:27371-27375.


CA-125: Uses

Detection

CA-125CA-125CA-125CA-125


CA-125 Level Variation in Ovarian Cancer

Characteristic Variation (N = 25)

Analytical imprecision, % 12.1

Intraindividual biological variation, % 24.0

Interindividual biological variation, % 43.1

Index of individuality 0.62

Tuxen MK, et al. Scand J Clin Lab Invest. 2000;60:713-721.


CA-125Doubling Median: 1.5 mos

CA-125 “lead time”: 3 mos

Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. Rustin GJ, et al. J Clin Oncol. 2001;19:4054-4057.

Recurrent Ovarian Cancer: Diagnosis

25

20

15

10

5

0

Pat

ien

ts (

n)

-12 -11-10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12

Mos From Clinical Progression

12

13

13 3

24 4

7

16

20

7

31 1 1


EORTC 55955: Schema

Previous ovarian, PP, tubal cancer

Previous platinum chemoNormal CA-125 following

first treatment

Conventional Surveillance (“Early”)

Blinded CA-125 q3mos

Monitored CA-125 (“Delayed”)If elevated, repeat in 4 wks

Confirmed elevation promptsChemotherapy

RANDOMIZE

Accrual goal: 1400

Objectives: OS, TFS, QoL


0

0.25

0.50

0.75

1.00

Pro

po

rtio

n A

live

No

t S

tart

ed S

eco

nd

-Lin

e C

hem

oth

erap

y

264 177 116 91 69 56 49 42 33Delayed265 23 16 14 11 11 10 10 9Early

Patients at Risk, n

0 3 6 9 12 15 18 21 24


When to Treat?

Median, MosEarly 0.8Delayed 5.6HR: 0.29 (95% CI: 0.24-0.35; P < .00001)

Rustin G, et al. ASCO 2009. Abstract 1. Reprinted with permission from the author.

Time From Randomization to Second-Line Chemotherapy


264 236 203 167 129 103 69 53 38 31 19265 247 211 165 131 94 72 51 38 31 22

Rustin G, et al. ASCO 2009. Abstract 1. Reprinted with permission from the author.

DelayedEarlyPatients at Risk, n


Pro

po

rtio

n S

urv

ivin

g

6 12 18 24 30 36 42 48 54 60

HR: 1.00 (95% CI: 0.82-1.22; P = .98)

Abs diff at 2 yrs: -0.1% (95% CI diff: -6.8, 6.3%)

Early Delayed

0

0.25

0.50

0.75

1.00

0

Overall Survival


Primary Treatment

End of FrontlineTherapy

0 Mos 6 Mos 12 Mos

Refractory Resistant Sensitive

Our patient

Platinum Sensitivity


Pros & Cons of Treating CA-125 Increase

Cons

Potential Rx of false positives

No improvement in OS

Exhaust treatment options

Toxicity

Impaired QoL

Cost

No ideal agent available

May be homeopathic only

Pros

Stay ahead of disease

Improve survival?

Prevent symptoms

Maximize QoL

“Active approach” to care

Intuitive to do something

Minimize patient anxiety

Avoids patient “relocating”

Shortens visit time


Modifying Influences on Clinical Practice

Applicability of UK to US3rd Party Payers

New AgentsAdvocacy Groups

CA-125 and Rustin Data


Intervention

Paracentesis First-line treatment for ascites in ovarian cancer patients 1]

Most patients need regular paracentesis[2]

Pleurx catheter Enables patients to manage drainage from pleural effusion at home and reduces risk for septic complications[3]

IP chemotherapy Associated with many complications and toxicities[4]

Bevacizumab IP administration shown be safe and effective when administered to palliate symptoms in patients with refractory malignant ascites[5]

Catumaxomab Trifunctional anti-EpCAM x anti-CD3 antibody Associated with significant reduction in ascites flow rate in

ovarian cancer patients[6] and with longer puncture-free survival and time to next paracentesis[7]

1. Sehouli J. Symptomorientierte Therapien: Aszites. In: Multimodales Management des Ovarialkarzinoms. Sehouli J andLichtenegger W (eds.). Bremen: UNI-MED, pp. 129-134, 2006. 2. Adam R, Adam Y. J Am Coll Sur. 2004;198: 999-1011.3. Iyengar T, Herzog TJ. Am J Hosp Pallit Care. 2002;19:35-38. 4. Woopen H, Sehouli J. Anticancer Res. 2009;29:3353-3360.5. El-Shami, et al. ASCO 2007. Abstract 9043. 6. Burges A, et al. Clin Cancer Res. 2007;13:3899-3905. 7. Heiss MM, et al. Int J Cancer. 2010 Apr 27 [Epub ahead of print].

Management of Ascites


Conclusions: CA-125 in Ovarian Cancer

Nearly 70% of advanced stage cancers relapse

Many patients will have relevant marker—usually first sign of recurrence with 3 mos of lead time

Marker reliability influenced by biologics

Traditional monitoring paradigms have been challenged by recent phase III data

Reconciling contemporary data with needs of providers and patients during era of economic restraint remains problematic

Is UK data completely applicable to all non-UK populations?

Best Management Approaches for Patients With Platinum-Sensitive Recurrent Disease


Recurrent Ovarian Cancer: Effect of Platinum-Free Interval and Survival

0-3 Prog 0-3 Non-PD 3-12 Mos 12-18 Mos 18+ Mos

PFS, days 90 176 174 275 339

OS, days 217 375 375 657 957

Response, % 9 24 35 52 62

Day

sP

ercentag

e

Pujade-Lauraine E, et al. ASCO 2002. Abstract 829.

1000900800700600500400300200100

0

100908070605040302010

0

Who Are the Best Candidates?


Secondary Cytoreduction: Patients With Short PFIs Do Not Benefit? Patients (N = 106)

– Optimal (no visible tumor): 82%

– All cisplatin based

– PFI: 6 mos

Time to second surgery: 16.8 mos (range: 6-109)

6-12 mos13-36 mos> 36 mos

Eisenkop SM, et al. Cancer. 2000;88:144-153.

1.00.90.8

0.70.60.50.4

0.30.2

0.10

0 12 24 36 48 60 72 84 96

Survival Time (Mos)

Cu

mu

lati

ve S

urv

ival

PFI = Platinum-free intervalPFI = Platinum-free interval


AGO DESKTOP OVAR II: Design

ECOG performance score: 0

No residuals after primary surgery (or, if unknown, initially FIGO I/II)

Absence of ascites > 500 mL

Predictive score positive (all items) ?

Yes

Surgery is planned?

Yes

Laparotomy

Platinum-based combination chemotherapy

No (basic collective 1)

No

Only descriptive analysis of further therapy


Complete resection in 76% of the study collective = AGO score could predict complete resection in at least 2 out of 3 patients

DESKTOP

Hypothesis

AGO DESKTOP OVAR II: Surgical ResultsFrequency of complete resection by applying the AGO score

100

90

80

70

60

50

40

30

20

10

0Score Positive:

All PatientsScore Positive:First Relapse

Score Positive:Second Relapse

75 7668

Harter P, et al. Ann Surg Oncol. 2006;13:1702-1710.


A randomized trial evaluating cytoreductive surgery in patients with platinum-sensitive recurrent ovarian cancer

Stratified byplatinum-free interval 6-12 vs > 12 mos,first-line platinum-

based chx: yes vs no

RANDOMIZE

Cytoreductivesurgery

Platinum-basedchemotherapy*recommended

*Recommended platinum-based chemotherapy regimens:

Carboplatin/paclitaxel

Carboplatin/gemcitabine

Carboplatin/pegliposomal doxorubicin

Or other platinum combinations in prospective trials

No surgery

AGO-OVAR DESKTOP III (Protocol AGO- OVAR OP.4)


Recurrent ovarian and peritoneal primary cancer TFI > 6 mos

Surgical candidate?

Yes No

Randomize Randomize

Surgery No surgery CarboplatinPaclitaxel

CarboplatinPaclitaxel

Bevacizumab

Maintenancebevacizumab

To chemotherapy randomization

GOG 213


Refractory

PREVIOUS

TREATMENT

Resistant

Sensitive

0 3 6 12 18 24

Time to Recurrence (Mos)

Very sensitive

Recurrent Ovarian Cancer: Definition of Disease Sensitivity


1978

Cis

plat

in

Car

bopl

atin

Altr

etam

ine

Pac

litax

elTo

pote

can

Lipo

som

al d

oxor

ubic

in (P

LD)

(acc

eler

ated

)Li

poso

mal

dox

orub

icin

(ful

l)

Gem

cita

bine

(with

car

bopl

atin

)

2006

1989

1990

1992

1996

1999

2005

2009

Trab

ecte

din;

EU

onl

y

(with

PLD

)

FDA-Approved Drugs in Ovarian Cancer

1964

Mel

phal

anD

oxor

ubic

in

1974


Decreased toxicity Decreased toxicity

Prolonged platinum-free intervalProlonged platinum-free interval

Alternative mechanism of actionAlternative mechanism of action

Potential Advantages to Nonplatinum Agents in Intermediately Sensitive Disease


Positive Trials in Recurrent Ovarian Cancer Paclitaxel vs topotecan[1,2]

Topotecan vs pegylated liposomal doxorubicin (PLD)[3,4]

Platinum vs platinum + paclitaxel[5]

Carboplatin vs carboplatin + gemcitabine[6]

Carboplatin + PLD vs carboplatin + paclitaxel[7]

PLD vs PLD + trabectedin[8]

1. ten Bokkel Huinink WW, et al. J Clin Oncol. 1997;15:2183-2193. 2. ten Bokkel Huinink WW, et al. Ann Oncol. 2004;15:100-103. 3. Gordon AN, et al J Clin Oncol. 2001;19:3312-3322. 4. Gordon AN, et al. Gynecol Oncol. 2004;95:1-8. 5. Parmar MK, et al. Lancet. 2003;361:2099-2106. 6. Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. 7. Vasey P, et al. ECCO ESMO 2009. Abstract 18LBA. 8. Monk BJ, et al. ESMO 2008. Abstract LBA4


Platinum vs Platinum + Paclitaxel

N = 802 (776 evaluable)

Platinum Platinum +Paclitaxel

P Value

Platinum sensitive, %

100 100

Response rate, %

54 66 .06

Median PFS, mos

9 12 .0004

Median OS, mos

24 29 .02

Parmar MK, et al. Lancet. 2003;361:2099-2106.Parmar MK, et al. Lancet. 2003;361:2099-2106.

SurvivalSurvival

PFSPFS1.0

0.8

0.6

0.4

0.2

00 1 2 3 4

Yrs From Randomization

Pro

po

rtio

n S

urv

ivin

g

Pro

gre

ssio

n F

ree Paclitaxel plus platinum

Conventional treatmentHR: 0.76 (0.66-0.89;P = .004)

1.0

0.8

0.6

0.4

0.2

00 1 2 3 5

Yrs From Randomization

Pro

po

rtio

n S

urv

ivin

g Paclitaxel plus platinum

Conventional treatmentHR: 0.82 (0.69-0.97; P = .023)

4


ICON 4: “A Mixed Bag”

Entry Criteria

TFI (median): not statedTFI > 12 mos for 75% (both arms)

*4% > 2.

Site Accrual Met?

PreviousTaxane?

TFI, Mos PreviousChemo

Meas. Disease

RelapseCriteria

MRC-CTU

Yes Not req. > 6 > 1* Not req. CA-125

IRFMN Yes Not req. > 12 1 Required Meas.

AGO No Required > 6 1 Not req. Meas.


Gemcitabine 1000 mg/m² Days 1, 8 Carboplatin AUC 4 Day 1

q3w for 6 cycles*

Carboplatin AUC 5 Day 1 q3w for 6 cycles*

Stratified by:

Platinum-free interval (6-12 or > 12 mos)

Type of first-line platinum therapy (platinum/paclitaxel or other platinum therapy)

Bidimensionally measurable disease (yes or no)

*Patients were treated for 6 cycles in the absence of progressive disease or unacceptable toxicity.

At investigator discretion, benefiting patients could receive a maximum of 10 cycles.

RA

ND

OM

IZE

D

Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707.

Phase III Trial of Carboplatin/Gemcitabine:

Study Design


Median PFSGemcitabine/

Carboplatin, MosCarboplatin, Mos

Progression-free interval

(6-12 mos)7.9 5.2

Progression-free interval

(> 12 mos)9.7 6.7

Previous platinum and paclitaxel 9.7 5.9

Previous platinum (no paclitaxel)

7.6 5.7

American Society of Clinical Oncology. ASCO Virtual Meeting 2003; Abstract and presentation 5005, slides 13-16.

Phase III Registration Trial Carbo/Gem: Prespecified Subgroup Analysis for PFS


PLD 30 mg/m² 90-min infusion followed by

Trabectedin* 1.1 mg/m² 3-hr infusion q3w

PLD 50 mg/m2 90-min infusion q4w

RANDOMIZATION

OVA-301: Study Design

*Premedication with dexamethasone is required.

Monk BJ, et al. J Clin Oncol. June 1, 2010 [Epub ahead of print].


OVA-301: PFS Primary Endpoint by Independent Radiologist—Measurable*

PFS events: 389HR: 0.79 (0.65-0.96; P = .0190)# censored: 256

Trabectedin + PLD 7.3 mosPLD 5.8 mos

*27 subjects nonmeasurable (9 trab + PLD [2 not treated], 18 PLD [1 not treated])

Pa t

ien

ts (

%)

PFS (Mos)


100

90

80

70

60

50

40

30

20

10

00 2 4 6 8 10 12 14 16 18 20 22 24 26 28

Patients at Risk, nPLDTrabectedin/PLD

317328

208225

139176

93121

5486

3563

2233

1422

613

410

07

06

04

00

00


PFS events: 226HR: 0.73 (0.56-0.95; P = .0170)# censored: 191

Trabectedin + PLD 9.2 mos

PLD 7.5 mos

Su

bje

cts

(%

)

*9 not treated and 18 nonmeasurable.

100

90

80

70

60

50

40

30

20

10

00 2 4 6 8 10 12 14 16 18 20 22 24 26 28

Patients at Risk, nPLDTrabectedin/PLD

202215

138164

102133

71102

4572

3056

1730

1120

513

310

07

06

04

00

00

PFS (Mos)

OVA-301: PFS (PFI > 6 Mos) by Independent Radiologist (All Measurable* Subjects)



Favorable Opinion for Trabectedin by EMEA September 24, 2009: The EMEA Committee for Medicinal

Products for Human Use (CHMP) adopted a positive opinion to recommend the variation to the terms of the marketing authorization for the medicinal product trabectedin. The CHMP adopted a new indication as follows:

– “[Trabectedin] in combination with pegylated liposomal doxorubicin (PLD) is indicated for the treatment of patients with relapsed platinum-sensitive ovarian cancer”

EMEA. Available at: http://www.emea.europa.eu/pdfs/human/opinion/Yondelis_60855009en.pdf.


OVA-301: Results Among Partially Sensitive Subpopulation

Poveda A, et al. ASCO 2010. Abstract 5012.

Measure Trabectedin + PLD PLD P Value

Response rate,* % 33 15 .0041

Median PFS,* mos 7.4 5.5 .00152 (HR, 0.65)

Median OS, mos 20.7 17.2 .0090 (HR, 0.59)

Time from randomization to subsequent platinum-based therapy, mos

15.3 11.6 .0093 (HR, 0.60)

*By independent radiologist review


PLD + Carbo in Ovarian Cancer Pts Who Recur Within 6-12 Mos: Phase II Study PLD 30 mg/m2 followed by carboplatin AUC 5 mg/mL/min every 4 wks

N = 54

75% received at least 6 cycles

RECIST RR: 46% (4% CR and 42% PR)

– Additional 33% experiencing disease stabilization > 6 mos

CA-125 RR: 66% (28% CR and 38% PR)

– Additional 18% experiencing disease stabilization > 6 mos

Median TTP: 10.0 mos (range: 1.5-25.0)

Median OS: 19.1 mos (range: 2.2-38.9)

Most frequent adverse effects were neutropenia, thrombocytopenia, and constipation

Power P, et al. Gynecol Oncol. 2009;114:410-414.

CALYPSO TrialCarboplatin + PLD vs

Carboplatin + Paclitaxel in Relapsed, Partially Platinum-

Sensitive Ovarian CancerPaul Vasey

on behalf of all GCIC collaboratorsECCO ESMO 2009


CALYPSO Study Schema

International, Intergroup, Open-label, Randomized Phase III Study

Ovarian cancer in relapse > 6 mos

after first- or second-line platinum + taxane

chemotherapy

RANDOMIZE

Experimental arm: CDPLD 30 mg/m2 IV Day 1

Carboplatin AUC 5 Day 1

q28 days x 6 courses*

Control arm: CPPaclitaxel 175 mg/m2 IV Day 1

Carboplatin AUC 5 Day 1

q21 days x 6 courses*

*Or progression in patients with SD or PR.

Stratification

Center

Measureable disease(yes vs no)

Therapy-free interval(6-12 mos vs > 12 mos)


Accrual

AGO-OVAR (Germany), GINECO (France, Switzerland, Turkey, Saudi Arabia), NSGO (Denmark, Finland, Norway, Sweden), NCIC-CTC (Canada), ANZGOG (Australia, New Zealand), AGO (Austria), EORTC (Netherlands, Belgium, Spain), MITO (Italy), MANGO (Italy)

Treatment Total

Therapy-Free Interval CD, n (%) CP, n (%)

6-12 mos 161 (35) 183 (36) 344 (35)

> 12 mos 305 (65) 326 (64) 631 (65)

Vasey P, et al. ECCO ESMO 2009. Abstract 18LBA.


Progression-Free Survival (ITT):Primary Endpoint

Vasey P, et al. ECCO ESMO 2009. Abstract 18LBA. Reprinted with permission from the author.

CD CP

Median PFS, mos 11.3 9.4

HR (95% CI) 0.82 (0.72-0.94)

Log-rank P value (superiority)

.005

P value (noninferiority) < .001

1.0

0.8

0.6

0.4

0.2

00 6 12 18 24 30

Pro

po

rtio

n n

ot

Pro

gre

ssin

g

Mos From Randomization

CP

CD

Patients at Risk, nCDCP

467509

397405

188152

6045

2010

42


CD CP

Median PFS, mo 9.4 8.8

HR (95% CI) 0.73 (0.58, 0.90)

Log-rank P-value (superiority)

0.004

P-value (non-inferiority) <0.001

PFS 6-12 Month Segment

Vasey P, et al. ECCO ESMO 2009. Abstract 18LBA. Reprinted with permission from the author.


Cediranib (AZD 2171)*

Cediranib is a tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, and c-kit

Blocking VEGFR-2 inhibits VEGF signaling, angiogenesis, and tumor growth

Highly potent

Orally bioavailable

Toxicity: hypertension, fatigue, diarrhea, nausea

Wedge SR, et al. Cancer Res. 2005;65:4389-4400.

*AZD 2171 is an investigational agent.


Cediranib (AZD 2171)*

Phase II study in recurrent EOC or peritoneal or fallopian tube cancer

N = 46

RR: 8 (17%; 95% CI: 7.6% to 30.8%)

– All PRs, no CRs

Median PFS: 5.2 mos

Median OS not reached

Grade 4 toxicities

– CNS hemorrhage (n = 1)

– Hypertriglyceridemia/hypercholesterolemia/elevated lipase (n = 1)

– Dehydration/elevated creatinine (n = 1)

Grade 3 toxicities (> 20% of pts)

– Hypertension (46%)

– Fatigue (24%)

– Diarrhea (13%)

Grade 2 hypothyroidism occurred in 43% of patients

No bowel perforations or fistulas occurredMatulonis UA , et al. J Clin Oncol.

2009;27:5601-5606.

*AZD 2171 is an investigational agent.


Patients with platinum-sensitive ovarian cancer

Relapsed > 6 mos following first-line platinum-based

treatment

Measurable disease

(N = 33)*

*Planned: phase II (N = 300), phase III (N = 2000).

Platinum-based chemotherapy(± taxane) q21 days x 6 cycles+ oral Cediranib daily during

chemo, then 18 mos of Placebo

Platinum-based chemotherapy(± taxane) q21 days x 6 cycles

+ Placebo

Platinum-based chemotherapy (± taxane) q21 days x 6 cycles+ oral Cediranib during chemoand until progression or 18 mos

Randomized 2:3:3


ICON 6 (Second-Line European Trial)


Recurrent Ovarian and Peritoneal Primary Cancer TFI > 6 mos

Surgical Candidate?

Yes No

Randomize Randomize

Surgery No Surgery CarboplatinPaclitaxel

CarboplatinPaclitaxel

Bevacizumab

MaintenanceBevacizumab

To Chemotherapy Randomization

GOG 213


Management of Patients in Challenging Clinical Situations: Platinum Resistance and Other Clinical Scenarios


Case #3: Treatment History

Symptoms

Diagnosis

Staging

?5

mos

Progression

Now What?

Primary Chemo x 6

RecurrentChemo x 6


Treatment Considerations

Recognize her situation is not curable but treatable

Survey carefully for pre-existing toxicities

Assess her likelihood for response

Develop your approach:

– Standard: NCCN guidelines

– Experimental: Clinical study


Practice Guidelines (2010)

Pts with PD, SD, or persistent disease receiving primary chemotherapy should receive

– Supportive care

– Recurrence therapy

– Referral to a clinical trial

Pts achieving CR and relapse within 6 mos following chemotherapy OR pts with stage II-IV disease with PR should receive

– Observation

– Recurrence therapy (such as with non-platinum-based single agent therapy)

– Referral to a clinical trial

NCCN Clinical Practice Guidelines in Oncology. Ovarian Cancer v.2.2010. NCCN Clinical Practice Guidelines in Oncology. Ovarian Cancer v.2.2010.


NCCN. Clinical Practice Guidelines in Oncology. Ovarian Cancer v.2.2010.

Practice Guidelines (2010): Recurrence Therapies — Preferred Regimens Cytotoxic regimens

Targeted therapy: Bevacizumab

Platinum-resistant diseaseSingle-agent (non-platinum based)PLDDocetaxelGemcitabineEtoposide (oral)PemetrexedTopotecanPaclitaxel (wkly)


Summary of Phase III Single-Agent Trials: Recurrent Ovarian Cancer

Drug A Drug B N TTP (wks) P OS (wks) P Comment

Topotecan Paclitaxel 226 23 vs 14 NS 61 vs 43 NS 50% Cross-over

Paclitaxel (bolus)

Paclitaxel (weekly)

208 38 vs 26 NS 34 vs 59 NS Less toxicity w/ weekly

Oxaliplatin Paclitaxel 86 12 vs 14 NS 42 vs 37 NS 74% platinum resistant

PLD Topotecan 481 16 vs 17 NS 60 vs 57 NS 54% platinum resistant; OS

benefit in platinum-sensitive subgroup

PLD Paclitaxel 214 22 vs 22 NS 46 vs 56 NS All pts taxane-naive

Topotecan Treosulfan 357 22 vs 12 .001 56 vs 48 .02 2nd – 3rd line therapy

PLD Gemcitabine 195 16 vs 13 NS 59 vs 55 NS

PLD Gemcitabine 153 16 vs 20 NS 55 vs 50 NS 56% platinum resistant

PLD or Topotecan

Canfosfamide 461 19 vs 9 < .01 59 vs 37 (PLD: 62 vs Topo: 47)

< .0001 ASSIST-1 trialAll 3rd line


Chemoresistant Queue GOG126: Taxanes

Drug Study N RR, % PFS (mos) OS (mos)

Docetaxel 126-L 58 22 2.1 12.7

Paclitaxel wkly 126-N 48 21 3.6 NS

nab-paclitaxel 126-R 51 23 4.5 17.4

Paclitaxel poliglumex

186-C 49 16 2.8 15.4

Controversial: Taxane-free interval – effect not observed in GOG 126-L


Pemetrexed

Anti-folate

– Approved in malignant mesothelioma and advanced or metastatic NSCLC

– Enters via reduced folate carrier and a selective high capacity transporter

– Active against DHFR, TS, GARFT

Phase II study

– GOG 126-Q

N-[4-[2-(2-amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-

yl)ethyl]benzoyl]-L-glutamic acid


Pemetrexed in Ovarian Cancer

GOG 126-Q Characteristic Tox Heme (Gr 3/4)

N 48 ANC: 42%

Patients Plat-R, measurable RBC: 15%

No. of chemo lines 1 Platelets: 13%

Regimen 900 mg/m2 IV (21 d) Constitutional: 15%

Response (%) Non-Heme (Gr 3/4)

CR+PR 1(2%)+9(19%): 21% GI/Nausea: 15%

SD 17 (35%) Neuro: 10%

PFS/OS 2.8 mos/11.4 mos Alopecia (Gr 2): 10%

Miller DS, et al. ASCO 2009. Abstract e16507.


Chemotherapy vs Hormones

PFS

Chemotherapy (PLD vs Pac-Wkly)

Tamoxifen

OS

Chemotherapy (PLD vs Pac-Wkly)

Tamoxifen

328 d vs 278 dP = .56

87 d vs 62 dP = .024

Kristensen GB, et al. IGCS 2008. Abstract 2008_1175.Kristensen GB, et al. IGCS 2008. Abstract 2008_1175.

N = 241 platinum/taxane-resistant

0 10 20 30 40months

0.00

0.25

0.50

0.75

1.00

0 10 20 30 40months

0.00

0.25

0.50

0.75

1.00

50


PLD + Trabectedin vs PLD: Phase III Registration Trial Recurrent ovarian cancer

– One prior regimen

– Evaluable and measurable disease

– Platinum sensitive and resistant

Accrual goal: 650 patients

Primary endpoint: OS

Other endpoints: PFS, RR, safety

Translational research– Pharmacokinetics

– Pharmacogenomics

– Pharmacoeconomics

– Quality of life

– Circulating tumor cells

RANDOMIZE

PLD 50 mg/m2 q 4 wks

PLD 30 mg/m2 + q3 weeksTrabectedin 1.1 mg/m2

Monk BJ, et al. J Clin Oncol . June 1, 2010 [Epub ahead of print].


OVA-301: PFS (TFI < 6 mos)

Trabectedin+PLD4.0 mos

PLD3.7 mos

PFS events: 163HR: 0.95 (0.70-1.30)P =.7540# censored: 65

Progression-free survival (months)RR: 12% vs 13% (rad review)

0 4 8 14 280

10

50

70

1.00

90

80

60

20

30

40

262422201816121062

Per

cen

t o

f S

ub

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ts

No. Subjects at Risk

PLDTrabectedin/PLD

115 37 9 3 0000011552270113 43 14 2 00000001371961



GOG 170 Series: Track Record

Response Rate (%)Response Rate (%)

PF

S ≥

6 (

%)

PF

S ≥

6 (

%)

Bevacizumab

VorinostatVorinostatLapatinibLapatinib

GefitinibGefitinibImatinibImatinib

SorafenibSorafenib TemsirolimusTemsirolimus

EnzastaurinEnzastaurinMifepristoneMifepristone


Phase II Studies of Bevacizumab in Recurrent Ovarian CancerMeasure, % Cannistra et al[1]

(N = 44)Garcia et al[2]

(N = 70)Burger et al[3]

(N = 62)

Previous regimens

1 100% 34%

2 52% 66%

3 48%

Response rate

CR 0% 0% 3%

PR 16% 24% 18%

Gastrointestinal perforations 11% 6% 0%

Arterial thrombosis 7% 4% 0%

Bevacizumab-related deaths 7% 4% 0%

1. Cannistra SA, et al. J Clin Oncol. 2007;25:5180-5186. 2. Garcia AA, et al. J Clin Oncol. 2008;26:76-82.3. Burger RA, et al. J Clin Oncol. 2007;25:5165-5171.


Platinum-Sensitivity and Bevacizumab

Parameter Wald P HR (95% CI)

GOG PS > 0 vs 0

0.25 1.49 (0.76-2.9)

Plat-S Y vs N

0.47 0.80 (0.44-1.46)

Age 0.91 1.0 (0.98-1.02)

Prior chemo 2 vs 1

0.12 0.62 (0.33-1.14)

0 6 12 24 30Time Since Start of Bevacizumab +

Cyclophosphamide Treatment (months)

0

0.1

0.4

0.8

1.0

18

0.20.3

0.5

0.6

0.9

0.7

Est

ima

ted

Pro

bab

ilit

y o

fP

rog

ress

ion

-Fre

e S

urv

ival

Platinum-sensitive (n=42)Platinum-resistant (n=28)All patients (n=70)Log-rank P=.004

Burger RA, et al. J Clin Oncol. 2007;25:5165-5171. Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. Garcia AA, et al. J Clin Oncol. 2008;26:76-82. Garcia AA, et al. J Clin Oncol. 2008;26:76-82. Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved.

GOG-170D (Burger et al.) (Garcia, et al.)


Toxicity from Target and Off Target Constituents Hypertension

– CNS

Proteinuria

Cardiac:

– CHF

– Conduction abnormalities

Endocrine

– Thyroid

VTE

– Arterial and venous

Hemorrhage

GI toxicity

– Perforation

– Fistula

Dermatologic

– Rash

– Wound disruption


Extraluminal Air


Morbid situation

– Mortality > 50%

– Challenging counseling due to several factors such as disease status, patient’s intentions, clinical condition at presentation

Management approach (discontinue agent) and:

– Non-interventional: comfort care

– Conservative care: observation, nutritional support, octreotide, drains, antibiotics

– Surgical: intestinal resection/bypass, stomata…

(~5% incidence in recurrent population)

Treatment-Emergent Toxicity: Perforation


Poly (ADP-Ribose) Polymerase (PARP)

If PARP is inhibited, SSB repair prevented, leading to increased double strand DNA breaks


Clinical Activity: Phase I

Fong PC, et al. ASCO 2008. Abstract 5510.


Phase II Trial Olaparib in BRCA-Deficient Recurrent Ovarian Cancer: Efficacy

Audeh MW, et al. ASCO 2009. Abstract 5500.

Patients with confirmed BRCA 1/2 mutation, recurrent (stage IIIB/IIIC/IV) ovarian cancer after failure of ≥ 1 platinum-based chemotherapy


PARPi Trials: Ongoing/Planned

17 ovarian trials listed on Clinicaltrials.gov Web site

PARP agents

– AG014699

– Olaparib

– BSI-201

– MK4827

– ABT-888

Single agent and in combination with chemo

Populations

– Known BRCA germline

– High grade serous

– 20-30% HR dysfunction


Investigational Agents

Biologics

AMG-386 (Tie2)

Pazopanib

BIBF-1120

IMC-1121B

Fosbretabulin

IMC-3G3

IGF-1R inhibitors

Rapalogs

PARPi

Chemotherapy and Others

Epothilones

– Ixabepilone

BMP-1350 (karenitecan)

NKTR-102

EC-145

Farletuzumab


NKTR-102: Peg-Irinotecan

Data on file. Nektar Therapeutics.

Platinum-resistant

ovarian cancer patients

(N = 70)

Primary Endpoint: Objective response

rate (GCIG)

145 mg/m2 q14d

145 mg/m2 q21d

Stage I N = 20/ regimen

Stage 2 N = 15/ regimen

Prior to entering the study:77% of patients in first stage progressed within 3 months of the last platinum dose

44% of patients in the first stage progressed within 3 weeks of the last platinum dose

Response Measure, % Confirmed Response

q14d q21d

GCIG response rate (RECIST and CA-125) 32 (6/19) 35 (7/20)

RECIST response rate 21 (4/19) 22 (4/18)

Preliminary results from first 39 patients in study*

*Full results for 71 patients to be presented at ASCO Annual Meeting, Sunday, June 6, 2010, 11:15 am (Vergote I, et al, Abstract 5013).


Utilizing the Folate Receptor: EC145

Folate-Vinca conjugate

Relevant for imaging targeting and therapy

Reddy JA, et al. Cancer Res. 2007;67:4434-4442.


EC145: Novel Folate Receptor Targeted Therapeutic Randomized Phase II, Platinum-resistant ovarian

Prior therapy: no more than 2 priors

Regimen:

– PLD 50 mg/m2 IBW q 28 days

– PLD 50 mg/m2 IBW q 28 days + EC145 2.5 mg weeks 1 and 3 (cycle: 28 days)

Toxicity similar in both arms: total AEs, SAEs, TETs

Naumann W, et al. ASCO 2010. Abstract LBA5012b.

Arm PFS HR P

PLD 11.7 wks - -

PLD+EC145 24.0 wks 0.497 0.014


Developmental Strategies

Chemotherapy with biologics

Chemotherapy combinations

Biological combinations

Patient profiling – biomarker driven design


Recommendations: Therapy

My bias would be to first consider a clinical trial such as 126 series or biologic 170-series

Off-protocol: a taxane vs PLD vs topotecan

– Decision based on antecedent toxicity, patient schedule preference, insurance

In the absence of CR or toxicity, treat to progression

– Wait for definitive evidence of progression

– CA-125 trends may be discordant to efficacy determination

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